The Th1/Th2 cytokine balance is believed to be a prominent factor in determining susceptibility, progression and prognosis in autoimmune diseases. It remains unclear which subset of Th cells play a more critical role in systemic autoimmune diseases such as SLE. Inconclusive results obtained so far suggest that both Th1 and Th2-type cytokines may be involved, and that the regulatory roles of such cytokines are very complex. The hypothesis we would like to explore in the present application is that the systemic autoimmune disease SLE is a multistage disease process in which Th1 and Th2 cytokines effect different aspects and different stages of disease development. We propose a genetic approach to study the mechanisms of autoimmune disease development employing a novel set of genetically manipulated mice. Signal transducers and activators of transcription (STAT) proteins are a class of transcription factors responsible for mediating many cytokine-induced responses. Recently, several groups have produced mice that lack one or the other Stat gene. The Stat-4 knockout mice are deficient in IL-12 functions including IFNg induction and Th1 differentiation. The Stat-6 knockout mice, on the other hand, are deficient in IL4 induced functions including Th2 differentiation. We have genetically transferred Stat-4 and Stat-6 null mutations onto the lupus susceptibility background of (NZBXNZW)Fl which is arguably the best available animal model for SLE. For this purpose two New Zealand Mixed congenic strains, NZM2410 and NZM2328, were used and four novel knockout mouse lines were created, the Stat4-/-. NZM2410, the Stat6-/-.NZM2410, the Stat4-/-.NZM2328 and the Stat6-/-.NZM2328, employing a marker-assisted selection protocol (MASP) strategy to accelerate and control the development of the desired congenic mice strains. In the proposed studies, we intend to characterize the development and progression of autoimmune disease in these four genetically manipulated new mouse lines, and to evaluate immune regulatory mechanisms pertinent to the development of autoimmunity. This application integrates the talents of a multidiscipline team combining expertise in genetics and cytokine biological aspects of autoimmune disease development (Dr. Jacob's group) with expertise in the B cell immunology and autoantibodies (Dr. Reeves' group) and T and NK cell immunobiology (Dr. Dennert's group).